Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models
Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models
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DOI：
10.1128/aac.49.6.2294-2301.2005
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发表时间：
2005-06-01
影响因子：
4.9
通讯作者：
Orme, IM
中科院分区：
文献类型：
--
作者：
Lenaerts, AJ;Gruppo, V;Orme, IM
这项研究延续了早期关于硝基咪唑并吡喃PA-824体外和体内抗结核效果的报道。PA-824对广泛的多重耐药临床分离株进行了体外试验，发现对所有分离株(MIC<；1µg/ml)都有很高的活性。在缺氧条件下，对PA-824的抗结核活性进行了评价。PA-824在2、10、50mU g/ml浓度下表现出与甲硝唑相似的活性，并呈剂量依赖关系。在短程小鼠感染模型中，将PA-824按50、100和300 mg/kg的体重以甲基纤维素或环糊精/卵磷脂配制，经9次口服治疗后，与异烟肼、利福平和莫西沙星的疗效进行比较。PA-824在100 mg/kg的环糊精/卵磷脂溶液中的活性与100 mg/kg的莫西沙星和25 mg/kg的异烟肼相当，略高于20 mg/kg的利福平。长期给予PA-824 100 mg/kg环糊精/卵磷脂治疗，可使肺和脾中的细菌负荷量降低到500cfu以下。PA-824与其他单一药物处理(异烟肼25 mg/kg、利福平10 mg/kg、加替沙星100 mg/kg、莫西沙星100 mg/kg)的活性没有显著差异。总之，PA-824在体内模型中的良好活性，以及对耐多药结核分枝杆菌和潜在潜伏状态的结核分枝杆菌分离株的活性，使PA-824成为治疗结核病的有吸引力的候选药物。这些数据表明，PA-824口服有效治疗结核病的潜力很大。
This study extends earlier reports regarding the in vitro and in vivo efficacies of the nitroimidazopyran PA-824 against Mycobacterium tuberculosis. PA-824 was tested in vitro against a broad panel of multidrug-resistant clinical isolates and was found to be highly active against all isolates (MIC < 1 mu g/ml). The activity of PA-824 against M. tuberculosis was also assessed grown under conditions of oxygen depletion. PA-824 showed significant activity at 2, 10, and 50 mu g/ml, similar to that of metronidazole, in a dose-dependent manner. In a short-course mouse infection model, the efficacy of PA-824 at 50, 100, and 300 mg/kg of body weight formulated in methylcellulose or cyclodextrin/lecithin after nine oral treatments was compared with those of isoniazid, rifampin, and moxifloxacin. PA-824 at 100 mg/kg in cyclodextrin/lecithin was as active as moxifloxacin at 100 mg/kg and isoniazid at 25 mg/kg and was slightly more active than rifampin at 20 mg/kg. Long-term treatment with PA-824 at 100 mg/kg in cyclodextrin/lecithin reduced the bacterial load below 500 CFU in the lungs and spleen. No significant differences in activity between PA-824 and the other single drug treatments tested (isoniazid at 25 mg/kg, rifampin at 10 mg/kg, gatifloxacin at 100 mg/kg, and moxifloxacin at 100 mg/kg) could be observed. In summary, its good activity in in vivo models, as well as its activity against multidrug-resistant M. tuberculosis and against M. tuberculosis isolates in a potentially latent state, makes PA-824 an attractive drug candidate for the therapy of tuberculosis. These data indicate that there is significant potential for effective oral delivery of PA-824 for the treatment of tuberculosis.